Randomized Comparison of 4-Times-Daily Versus Once-Daily Intravenous Busulfan in a Conditioning Therapy for Hematopoietic Cell Transplantation (HCT).

Several single-arm studies have shown that once-daily or twice-daily intravenous busulfan (iBU) may be equally safe and effective compared to traditional 4-times-daily iBU. We performed a prospective randomized trial of 4-times-daily vs. once-daily dosing of iBU in a conditioning therapy for HCT, and compared pharmacokinetic (PK) characteristics of iBU and clinical outcomes in terms of engraftment, post-HCT toxicities, non-relapse mortality (NRM), and overall survival. All of 60 patients, who received iBU on the first day of conditioning therapy for HCT, were randomized to receive iBU either as 0.8 mg/kg over 2 hr 4 times a day (BU4 arm) or 3.2 mg/kg over 3 hr once a day (BU1 arm) between May 2004 and August 2005. Limited sampling strategy was used for PK studies, which were done for the first busulfan dosing. Baseline patient and donor characteristics were well balanced between 2 arms regarding sex, age, diagnosis of underlying disease, time from diagnosis to HCT, disease status at HCT, GVHD prophylaxis regimen, conditioning therapy regimen, ABO mismatch between donor and recipient, donor-recipient sex pair, donor age, type of graft, donor type, and cell doses of graft. The complete PK data were obtained from all 60 patients and those were comparable between 2 arms: elimination half-life (mean ± SD) was 2.75 ± 0.22 vs. 2.83 ± 0.21 hr in BU4 arm vs. BU1 arm, respectively (P=0.304), estimated AUC was 7933.43 ± 2177.71 vs. 8556.86 ± 2452.07 μM × min per day (P=0.367), and clearance was 2.05 ± 0.36 vs. 1.91 ± 0.31 ml/min/kg (P=0.133). Median times to engraftment of neutrophils (BU4 arm vs. BU1 arm, 14 vs. 14 days, P=872) and platelets (26.5 vs. 25.5 days, P=0.946) after HCT were similar between 2 arms. There were no significant differences in cumulative incidence of acute GVHD (BU4 arm vs. BU1 arm, 31.0% vs. 13.8%, P=0.145) and occurrence of CMV infection (40.0% vs. 23.3%, P=0.165) or hepatic veno-occlusive disease (10.0% vs. 16.7%, P=0.448). Other toxicities within 100 days after HCT were not significantly different between two arms. Cumulative incidence of NRM was 25.5% vs. 17.3% (P=0.488) and overall survival probability at 1 year was 69.0% vs. 70.0% (P=0.758). In conclusion, our randomized study demonstrates that once-daily iBU has similar PK profiles and results in at least not inferior clinical outcomes compared to traditional 4-times-daily iBU.